Attenuated peptide YY release in obese subjects is associated with reduced satiety

The responses of the gut hormone peptide YY ( PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R-2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY1-36 to PYY3-36 was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY3-36 was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY3-36 in humans caused a graded reduction in food intake (R-2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY3-36 on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY3-36. Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY3-36 infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.